In medical and dental fields, there are many cases where a bone defect caused by a disease or injury must be repaired or regenerated. The first possible approach to repair the bone defect may be an autograft bone transplantation, but this approach causes problems including an invasion into the sound tissue owing to the autograft bone as well as quantitative and morphological limitation of the collected bone. Artificially produced bone substitute materials are therefore clinically employed.
It is desired for a bone substitute material to combine the features of (1) no histotoxicity, (2) osteoconductivity, (3) bone replacement capability, and (4) mechanical strength required in a bone reconstruction operation. No histotoxicity is indispensable to a biomaterial. Histotoxicity is evaluated from macroscopical or histopathological indication of inflammation in an experimental animal implanted with a bone substitute material. Histotoxicity is also influenced by the mechanical strength of a bone substitute material. There occurs crystalline inflammation if the mechanical strength of the bone substitute material is low so that the material is partly disintegrated during the bone reconstruction into powdery form and remains within the bone defect. Osteoconductivity is defined as the property of a bone substitute material applied to a bone defect to promote the formation of new bone tissue from the site of application to the bone so as to cover the bone substitute material. Osteoconductivity is a crucial property of a bone substitute material, the presence or absence of which is evaluated on histopathological examination of an experimental animal implanted with the bone substitute material. It is generally considered that if the differentiation of osteoblast cells cultured on a bone substitute material is promoted, then the material possesses osteoconductivity.
Bone replacement capability is crucial to a bone substitute material. In the bone replacement by the bone substitute material, it is ideal that the resorbing process by osteoclast cells and the bone formation process by osteoblast cells proceed as in the remodeling. Replacement of bone by the bone substitute material is histopathologically evaluated with an experimental animal implanted with the bone substitute material. However, the evaluation of the bone replacement capability with such experimental animals requires much time for the experiments. An osteoconductive material operates on the principle of replacing bone as resorption by osteoclast cells proceds. The possible bone replacement capability of such a material can therefore be ascertained by checking resorption cavities formed by the osteoclast cells on the material. It is also crucial for a bone substitute material to have the mechanical strength necessary for a bone repair operation. While the degree of the required mechanical strength is not necessarily definite, it is of course indispensable for the material to possess a mechanical strength resistant to the implantation.
Hydroxyapatite is currently the most-studied bone substitute material. The primary inorganic component of the bone, tooth or other hard tissue of verterbrates including humans is an apatite basically composed of hydroxyapatite, Ca10(PO4)6(OH)2. Thus, there is clinically used a bone substitute material composed of sintered hydroxyapatite prepared by sintering chemically synthesized hydroxyapatite. While sintered hydroxyapatite exhibits osteoconductivity and therefore is a very useful bone substitute material, it is an unresorbable material which will not be resorbed at bone defect sites even over the passage of time. Bone exhibits biological functions such as hematopoiesis, and it is ideal to use a bone substitute material which is capable of replacing bone.
Under the circumstances are also clinically used as bone substitute material such materials as β-tricalcium phosphate, calcium sulfate, calcium carbonate and the like. These materials exhibit resorbability but are not osteoconductive, or are less osteoconductive than hydroxyapatite. In addition, when there is used a resorbing material such as β-tricalcium phosphate, calcium sulfate or calcium carbonate, the resorption is caused by physicochemical dissolution or extraneous giant cells and the mechanism of the resorption is not linked with bone formation by osteoblast cells. Thus, in a case where bone defect is severe or the bone defect site is inferior in bone formation ability because of aging and other reasons, the bone resorption proceeds even before the bone formation is sufficiently carried out, resulting in the bone substitute material being consumed prior to its replacement of bone, and the bone defect comes to be repaired by fibrous connective tissue.
In the case of an autogenous bone transplantation, the mechanism of bone replacement by the transplanted bone is the same as that of the remodeling of living bone. Thus, bone resorption is advanced by osteoclast cells while bone formation is accomplished by osteoblast cells. In sintered hydroxyapatite which exhibits osteoconductivity, although the process of bone formation by osteoblast cells proceeds, no bone replacement occurs because bone is not resorbed by osteoclast cells. Resorption by osteoclasts is accomplished through the formation of Howship's lacunae, in the interior of which there is induced a low pH resulting in the decomposition of bone apatite. Bone apatite is carbonate apatite containing a carbonate group and therefore decomposable in the low pH environment induced by osteoclast cells. By contrast, since sintered hydroxyapatite contains no carbonate group, it is not decomposed in the low pH environment induced by osteoclast cells. Thus, sintered hydroxyapatie, which is currently put into clinical use as a bone substitute material, has no bone replacement capability partly because it is not a carbonate-containing apatite.
In view of there considerations, carbonate apatite would be an ideal bone substitute material. However, no technology for producing carbonate apatite practically utilizable as a bone substitute material has not been established. More specifically, known or proposed uses of carbonate apatite are limited to those as adsorbents or carriers for biomaterials and the like, and as restorative materials for bones and teeth [for example, Japanese Patent Application Publication No. 1995-61861 (Patent Reference No. 1), Japanese Patent Application Publication No. 1998-36106 (Patent Reference No. 2), Japanese Patent Application Publication No. 1999-180705 (Patent Reference No. 3)]. The latter use is only for the purpose of filling the defect sites of bones or teeth, and no material primarily composed of carbonate apatite has been developed which satisfies the prerequisites of a bone substitute material for medical use, including bone replacement capability and no histotoxicity without causing inflammation.    Patent Reference No. 1: Japanese Patent Application Publication No. 1995-61861    Patent Reference No. 2: Japanese Patent Application Publication No. 1998-36106    Patent Reference No. 3: Japanese Patent Application No. 1999-180705